STRUCTURAL BASIS FOR MAJOR HISTOCOMPATIBILITY COMPLEX (MHC)-LINKED SUSCEPTIBILITY TO AUTOIMMUNITY - CHARGED RESIDUES OF A SINGLE MHC BINDING POCKET CONFER SELECTIVE PRESENTATION OF SELF-PEPTIDES IN PEMPHIGUS-VULGARIS

Human T-cell-mediated autoimmune diseases are genetically linked to pa rticular alleles of MHC class II genes. Susceptibility to pemphigus vu lgaris (PV), an autoimmune disease of the skin, is linked to a rare su btype of HLA-DR4 (DRB10402, 1 of 22 known DR4 subtypes). The PV-linke d DR4 subtype differs from a rheumatoid arthritis-associated DR4 subty pe (DRB10404) only at three residues (DR beta 67, 70, and 71). The di sease is caused by autoantibodies against desmoglein 3 (DG), and T cel ls are thought to trigger the autoantibody production against this ker atinocyte adhesion molecule. Based on the DRB10402 binding motif, sev en candidate peptides of the DG autoantigen were identified. T cells f rom four PV patients with active disease responded to one of these DG peptides (residues 190-204); two patients also responded to DG-(206-22 0). T-cell clones specific for DG-(190-204) secreted high levels of in terleukins 4 and 10, indicating that they may be important in triggeri ng the production of DG-specific autoantibodies. The DG-(190-204) pept ide was presented by the disease-linked DRB10402 molecule but not by other DR4 subtypes. Site-directed mutagenesis of DRB10402 demonstrate d that selective presentation of DG-(190-204), which carries a positiv e charge at the P4 position, was due to the negatively charged residue s of the P4 pocket (DR beta 70 and 71). DR beta 71 has a negative char ge in DRB10402 but a positive charge in other DR4 subtypes, including the DR4 subtypes linked to rheumatoid arthritis. The charge of the P4 pocket in the DR4 peptide binding site therefore appears to be a crit ical determinant of MHC-linked susceptibility to PV and rheumatoid art hritis.